title: Solid-phase synthesis of 5'-triphosphate 2'-5'-oligoadenylates analogs with 3'-O-biolabile groups and their evaluation as RNase L activators and antiviral drugs.
abstract: 5'-Triphosphate 2'-5'-oligoadenylate (2-5A) is the central player in the 2-5A system that is an innate immunity pathway in response to the presence of infectious agents. Intracellular endoribonuclease RNase L activated by 2-5A cleaves viral and cellular RNA resulting in apoptosis. The major limitations of 2-5A for therapeutic applications is the short biological half-life and poor cellular uptake. Modification of 2-5A with biolabile and lipophilic groups that facilitate its uptake, increase its in vivo stability and release the parent 2-5A drug in an intact form offer an alternative approach to therapeutic use of 2-5A. Here we have synthesized the trimeric and tetrameric 2-5A species bearing hydrophobic and enzymolabile pivaloyloxymethyl groups at 3'-positions and a triphosphate at the 5'-end. Both analogs were able to activate RNase L and the production of the trimer 2-5A (the most active) was scaled up to the milligram scale for antiviral evaluation in cells infected by influenza virus or respiratory syncytial virus. The trimer analog demonstrated some significant antiviral activity.
authors.affiliation: IBMM, UMR 5247, CNRS-UM1-UM2, Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier, France.
authors.forename: Yann
authors.initials: Y
authors.lastname: Thillier
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Stevens
authors.forename: Christabel
authors.initials: C
authors.lastname: Moy
authors.forename: Joshua
authors.initials: J
authors.lastname: Taylor
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Vasseur
authors.forename: Leonid
authors.initials: L
authors.lastname: Beigelman
authors.forename: Françoise
authors.initials: F
authors.lastname: Debart
mesh_terms: D000227:Adenine Nucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004722:Endoribonucleases / Q000737:chemistry* / Q000378:metabolism; D031541:Fluorescence Resonance Energy Transfer; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects; D009843:Oligoribonucleotides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D058105:Polymerization; D060327:Solid-Phase Synthesis Techniques
chemical_list: D000227:Adenine Nucleotides; D000998:Antiviral Agents; D009843:Oligoribonucleotides; C023505:2',5'-oligoadenylate; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease
keywords: 2–5A analogs; 2′-5′-Oligoadenylate; Influenza virus; Pivaloyloxymethyl group; RNase L; Respiratory syncytial virus (RSV)